To the Editor:

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has globally disrupted contemporary life¹1. Munster VJ, Koopmans M, van Doremalen N, van Riel D, de Wit E. A novel coronavirus emerging in China – key questions for impact assessment. N Engl J Med. 2020;382(8): 692-4. https://doi.org/10.1056/NEJMp2000929
https://doi.org/10.1056/NEJMp2000929... . It has caused 73,996,237 confirmed cases and 1,663,474 deaths since December 19, 2020, with a global mortality rate of 2.25%²2. World Health Organization. WHO Coronavirus (COVID-19) dashboard. Geneva: World Health Organization; 2020. [cited on Dec. 19, 2020]. Available from: https://covid19.who.int/
https://covid19.who.int/... . While efforts to understand, cure, and prevent the disease are ongoing, the mortality rate and disease burden imposed by SARS-CoV-2, as well as the appropriateness of pandemic containment measures, are also being discussed³3. Parmet WE, Sinha MS. Covid-19 – the law and limits of quarantine. N Engl J Med. 2020;382(15): e28. https://doi.org/10.1056/NEJMp2004211
https://doi.org/10.1056/NEJMp2004211... ^–55. Kraemer MUG, Yang CH, Gutierrez B, Wu CH, Klein B, Pigott DM, et al. The effect of human mobility and control measures on the COVID-19 epidemic in China. Science. 2020;368(6490):493-7. https://doi.org/10.1101/2020.03.02.20026708
https://doi.org/10.1101/2020.03.02.20026... . To this end, geographic distributions of disease burden and disease-specific mortality are often key to understand disease vulnerabilities, formulate policies, and aid in opinion-making⁶6. GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390(10100):1211-59. https://doi.org/10.1016/S0140-6736(17)32154-2
https://doi.org/10.1016/S0140-6736(17)32... .

In this issue of Revista da Associação Médica Brasileira, Kant and colleagues report on their multi-center retrospective experience with 143 patients with H1N1 and 309 patients with SARS-CoV-2 from seven centers in Turkey⁷7. Kant A, Kostakoğlu U, Saral ÖB, Çomoğlu Ş, Arslan M, Karakoç HN, et al. Comparison of two pandemics: H1N1 and SARS-CoV-2. Rev Assoc Med Bras (1992). 2021;67(1):115-9. https://doi.org/10.1590/1806-9282.67.01.20200584
https://doi.org/10.1590/1806-9282.67.01.... . Among their pertinent findings related to the clinical profiling of the two diseases, one result is striking: in their hands, H1N1 was more lethal than SARS-CoV-2! In more detail, Kant et al⁷7. Kant A, Kostakoğlu U, Saral ÖB, Çomoğlu Ş, Arslan M, Karakoç HN, et al. Comparison of two pandemics: H1N1 and SARS-CoV-2. Rev Assoc Med Bras (1992). 2021;67(1):115-9. https://doi.org/10.1590/1806-9282.67.01.20200584
https://doi.org/10.1590/1806-9282.67.01.... . report that although H1N1 patients required fewer hospitalization days compared with SARS-CoV-2 patients (mean±SD: 4.4±5.7 versus 10.9±7.6 days; p<0.001; Mann-Whitney U test), they actually required more intensive care support (H1N1 versus SARS-CoV-2: 41 versus 18%; p<0.001; χ² test), more mechanical ventilatory support (H1N1 versus SARS-CoV-2: 28 versus 9%; p=0.004; χ² test), and succumbed more frequently (H1N1 versus SARS-CoV-2 mortality: 8.4 versus 3.2%; p=0.004; χ² test). Data from Turkey have been properly reported, are plausible, and in accordance with data from the United States reported earlier this year⁸8. Tang X, Du RH, Wang R, Cao TZ, Guan LL, Yang CQ, et al. Comparison of hospitalized patients with ARDS caused by COVID-19 and H1N1. Chest. 2020;158(1):195-205. https://doi.org/10.1016/j.chest.2020.03.032
https://doi.org/10.1016/j.chest.2020.03.... .

To put the work of Kant et al.⁷7. Kant A, Kostakoğlu U, Saral ÖB, Çomoğlu Ş, Arslan M, Karakoç HN, et al. Comparison of two pandemics: H1N1 and SARS-CoV-2. Rev Assoc Med Bras (1992). 2021;67(1):115-9. https://doi.org/10.1590/1806-9282.67.01.20200584
https://doi.org/10.1590/1806-9282.67.01.... into perspective, the author analyzed current SARS-CoV-2 data and compared them with global H1N1 data obtained after the end of the H1N1 pandemic, in the 27 most heavily affected countries (Table 1)²2. World Health Organization. WHO Coronavirus (COVID-19) dashboard. Geneva: World Health Organization; 2020. [cited on Dec. 19, 2020]. Available from: https://covid19.who.int/
https://covid19.who.int/... ^,99. Wikipedia contributors. 2009 swine flu pandemic by country. Wikipedia, The Free Encyclopedia; 2021. [cited on Dec. 20, 2020]. Available from: https://en.wikipedia.org/w/index.php?title=2009_swine_flu_pandemic_by_country&oldid=1032018082
https://en.wikipedia.org/w/index.php?tit... . According to the multi-center results provided by Kant et al.⁷7. Kant A, Kostakoğlu U, Saral ÖB, Çomoğlu Ş, Arslan M, Karakoç HN, et al. Comparison of two pandemics: H1N1 and SARS-CoV-2. Rev Assoc Med Bras (1992). 2021;67(1):115-9. https://doi.org/10.1590/1806-9282.67.01.20200584
https://doi.org/10.1590/1806-9282.67.01.... , nationwide, Turkish H1N1 death rates exceeded by far SARS-CoV-2 death rates, and this is also applicable to 12 other countries including the United States, Spain, and Brazil. However, the opposite was true for 15 other countries that experienced far higher death rates from SARS-CoV-2, such as Mexico, Egypt, China, and Italy. Overall, when the 27 countries that were most affected from both outbreaks were examined, death rates from SARS-CoV-2 and H1N1 were not statistically significantly different (Figure 1A). These data show that the study by Kant et al.⁷7. Kant A, Kostakoğlu U, Saral ÖB, Çomoğlu Ş, Arslan M, Karakoç HN, et al. Comparison of two pandemics: H1N1 and SARS-CoV-2. Rev Assoc Med Bras (1992). 2021;67(1):115-9. https://doi.org/10.1590/1806-9282.67.01.20200584
https://doi.org/10.1590/1806-9282.67.01.... is accurate in reflecting the Turkish experience from the two viral outbreaks, and that both pandemics cause comparable mortality, as anticipated for severe viral pneumonias.

Figure 1
Cases and deaths from SARS-CoV-2 and H1N1 in 27 countries.

But how can the astonishing fact that SARS-CoV-2 is less lethal than H1N1 in at least 12 countries be associated with a response that has been disproportionately greater, with stricter measures, and economic stagnation worldwide and in these countries (including in Brazil and Turkey) due to SARS-CoV-2 as compared to twhe H1N1 outbreak 11 years ago? Table 1 and Figure 1B illustrate the answer, which is the disproportional size of both outbreaks in terms of number of cases and deaths. To this end, H1N1 caused 6.14 million (16 thousand on average) cases and 227 thousand (593 on average) deaths in the 27 countries examined, while SARS-CoV-2 has already caused 56.7 million (1.3 million on average) cases and 2.1 million (47 thousand on average) deaths in the same countries, while the pandemic is still at large. Thus, one can argue that the SARS-CoV-2 outbreak has already taken a ten-fold higher toll than the H1N1 outbreak 11 years ago, underpinning its societal and financial impacts¹⁰10. Kaiser JC, Stathopoulos GT. Socioeconomic correlates of SARS-CoV-2 and influenza H1N1 outbreaks. Eur Respir J. 2020;56(3):2001400. https://doi.org/10.1183/13993003.01400-2020
https://doi.org/10.1183/13993003.01400-2... .

But what are the determinants of these strikingly different death rates? At a global scale, we have shown earlier this year that SARS-CoV-2 incidence and mortality are linked with economic growth, while H1N1 rates were rather associated with overpopulation and urbanization, like a true airborne disease¹⁰10. Kaiser JC, Stathopoulos GT. Socioeconomic correlates of SARS-CoV-2 and influenza H1N1 outbreaks. Eur Respir J. 2020;56(3):2001400. https://doi.org/10.1183/13993003.01400-2020
https://doi.org/10.1183/13993003.01400-2... . In an elegant recent prospective two-center case-control study, Sesé et al. showed the correlation between poor socioeconomic status and SARS-CoV-2 severity in terms of disease presentation and outcome¹¹11. Sesé L, Nguyen Y, Giroux Leprieur E, Annesi-Maesano I, Cavalin C, Goupil de Bouillé J, et al. Impact of socioeconomic status in patients hospitalised for COVID-19 in the Greater Paris area. Eur Respir J. 2020;56(6):2002364. https://doi.org/10.1183/13993003.02364-2020
https://doi.org/10.1183/13993003.02364-2... . It is also well known that co-morbidities largely define SARS-CoV-2 death rates, implying increased vulnerability of high-income countries with elderly populations to SARS-CoV-2¹²12. Guan WJ, Liang WH, Zhao Y, Liang HR, Chen ZS, Li YM, et al. Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis. Eur Respir J. 2020;55(5):2000547. https://doi.org/10.1183/13993003.00547-2020
https://doi.org/10.1183/13993003.00547-2... . To this end, biomarkers of SARS-CoV-2 susceptibility in elderly patients and populations with cardiovascular, cerebral, and pulmonary co-morbidities have been proposed, including low circulating CD3+CD8+T-cells and cardiac troponin¹³13. Du RH, Liang LR, Yang CQ, Wang W, Cao TZ, Li M, et al. Predictors of mortality for patients with COVID-19 pneumonia caused by SARS-CoV-2: a prospective cohort study. Eur Respir J. 2020;55(5):2000524. https://doi.org/10.1183/13993003.00524-2020.
https://doi.org/10.1183/13993003.00524-2... . One cannot overemphasize the importance of such clinical, cellular, and molecular biomarkers of risk, as well as of clinical studies such as that by Kant et al.⁷7. Kant A, Kostakoğlu U, Saral ÖB, Çomoğlu Ş, Arslan M, Karakoç HN, et al. Comparison of two pandemics: H1N1 and SARS-CoV-2. Rev Assoc Med Bras (1992). 2021;67(1):115-9. https://doi.org/10.1590/1806-9282.67.01.20200584
https://doi.org/10.1590/1806-9282.67.01.... , which will hopefully be considered by policy-makers and their health care advisors during future infectious outbreaks to prevent lockdown measures and economic recession, and to enforce viral containment measures that are more focused and effective.

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